Heart failure is an epidemic disease syndrome accompanied by a high mortality rate related to progressive myocardial dysfunction. Myocardial beta-adrenergic mechanisms are a potentially important component of the progressive natural history of heart failure. Cardiac adrenergic activation that increases as pump failure worsens produces two types of adverse effects on the heart: beta-receptor pathway desensitization phenomena, and toxic effects on the myocardium mediated by remaining pathway function. The former type of abnormality impairs exercise or stress responses, while the latter may cause worsening of myocardial dysfunction or arrhythmia. We do not fully understand how either type of abnormality occurs. THE PROBLEM is that work in this area has been limited by the lack of an appropriate model system. Over the past several years we have developed sophisticated methods of examining beta-adrenergic neuroeffector mechanisms in the intact failing human heart. Our ability to examine beta-adrenergic neuroeffector mechanisms in the intact human heart now approaches or exceeds the capability of performing these kinds of studies in animal models. OUR PRELIMINARY DATA indicate that: a) with an intracoronary isotopic technique we can measure interstitial norepinephrine concentration in the intact human heart; b) we can measure beta(1)- and beta(2)- adrenergic receptors in endomyocardial biopsy tissue, and in idiopathic dilated cardiomyopathy (IDC) this analysis is representative of right or left ventricular free wall; c) with a powerful new tool for quantifying mRNA (quantitative polymerase chain reaction) we can measure the steady-state level of mRNA in RNA extracted from endomyocardial biopsy tissue, for any cloned human gene. OUR OVERALL GOALS are to learn more about how chronic adrenergic activation leads to alterations in myocardial gene expression, and how beta-adrenergic blockade optimally improves cardiac function. In an IDC population we wish to elucidate: 1) if chronically increased levels of cardiac norepinephrine down-regulate cardiac myocardial beta(1)-adrenergic receptors by decreasing the steady-state level of beta(1) receptor mRNA; 2) if "atypical" beta-blocking agents fail to up-regulate beta(1)-adrenergic receptors because they do not up- regulate receptor mRNA; 3) the consequences of a beta-blocking agent not up-regulating the down-regulated beta-adrenergic receptor population in heart failure; 4) a phenotypic marker of failing myocardium, suitable as a molecular or biochemical marker of failing heart muscle. THE SIGNIFICANCE of this project is that a better understanding of how increased adrenergic drive affects gene expression and how to optimally inhibit increased adrenergic drive could lead to new therapeutic options for the treatment of heart failure.